rs56198613

chr7-92099740-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_005751.5(AKAP9):c.10767G>A(p.Leu3589=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,066 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: AKAP9 NM_005751.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.712

Genes affected

AKAP9 (HGNC:379): (A-kinase anchoring protein 9) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternate splicing of this gene results in at least two isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3. [provided by RefSeq, Aug 2008]

CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-92099740-G-A is Benign according to our data. Variant chr7-92099740-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197505.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}. Variant chr7-92099740-G-A is described in Lovd as [Benign]. Variant chr7-92099740-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.712 with no splicing effect.
• BS2: High AC in GnomAd at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP9	NM_005751.5	c.10767G>A	p.Leu3589=	synonymous_variant	44/50	ENST00000356239.8
AKAP9	NM_147185.3	c.10743G>A	p.Leu3581=	synonymous_variant	44/50
AKAP9	NM_001379277.1	c.5412G>A	p.Leu1804=	synonymous_variant	23/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP9	ENST00000356239.8	c.10767G>A	p.Leu3589=	synonymous_variant	44/50	1	NM_005751.5	P4

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00110 AC: 277 AN: 251380 Hom.: 1 AF XY: 0.00121 AC XY: 165 AN XY: 135864

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00145 AC: 2120 AN: 1461828 Hom.: 4 Cov.: 31 AF XY: 0.00146 AC XY: 1060 AN XY: 727218

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74440

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00202 Hom.: 4

Bravo AF: 0.00104

EpiCase AF: 0.00191

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	AKAP9: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2020	- -

Long QT syndrome 11 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Jun 28, 2017

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2015

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	6.7
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56198613; hg19: chr7-91729054;